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WO1996010026A1 - Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle) - Google Patents

Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle) Download PDF

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Publication number
WO1996010026A1
WO1996010026A1 PCT/EP1995/003690 EP9503690W WO9610026A1 WO 1996010026 A1 WO1996010026 A1 WO 1996010026A1 EP 9503690 W EP9503690 W EP 9503690W WO 9610026 A1 WO9610026 A1 WO 9610026A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
hydrogen
chloro
dihydro
Prior art date
Application number
PCT/EP1995/003690
Other languages
English (en)
Inventor
Jean-Paul René Marie André BOSMANS
Marc Gustaaf Celine Verdonck
Georges Henri Paul Van Daele
Original Assignee
Janssen Pharmaceutica N.V.
HENDRICKX, Marie-Louis
VAN DAELE, Kurt, Godfreid, Cornelius, Emile
VAN DAELE, Peter, Jules, Victor
VAN DAELE, Glenn, Kurt, Ludo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR9509035A priority Critical patent/BR9509035A/pt
Priority to DK95933399T priority patent/DK0784619T3/da
Priority to US08/809,502 priority patent/US5872131A/en
Priority to NZ293604A priority patent/NZ293604A/en
Priority to PL95319998A priority patent/PL182174B1/pl
Priority to AU36080/95A priority patent/AU702846B2/en
Priority to DE69508600T priority patent/DE69508600T2/de
Priority to CA002200579A priority patent/CA2200579C/fr
Priority to EP95933399A priority patent/EP0784619B1/fr
Priority to JP51133796A priority patent/JP3862750B2/ja
Application filed by Janssen Pharmaceutica N.V., HENDRICKX, Marie-Louis, VAN DAELE, Kurt, Godfreid, Cornelius, Emile, VAN DAELE, Peter, Jules, Victor, VAN DAELE, Glenn, Kurt, Ludo filed Critical Janssen Pharmaceutica N.V.
Priority to CZ1997919A priority patent/CZ288942B6/cs
Priority to MXPA/A/1997/002356A priority patent/MXPA97002356A/xx
Publication of WO1996010026A1 publication Critical patent/WO1996010026A1/fr
Priority to NO19971375A priority patent/NO311673B1/no
Priority to FI971273A priority patent/FI971273A/fi
Priority to GR990401260T priority patent/GR3030175T3/el

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention is concerned with novel benzoate derivatives, pharmaceutical compositions comprising said novel compounds, processes for preparing compounds and compositions, and the use thereof as a medicine, in particular in the treatment of conditions involving a decreased motility of the colon.
  • the present novel compounds show intestinal prokinetic activity.
  • the presently disclo.sed compounds show utility in treatment of conditions involving a decreased motility of the intestine, especially the colon.
  • the present invention is concerned with novel benzoate derivatives having the formula
  • R 1 is halo or Ci- ⁇ alkylsulfonylamino; either R2 is hydrogen and R 3 is C2-6al enyl or C2-6alkynyl; or
  • Alk is Ci ⁇ alkanediyl
  • R 4 is hydrogen or Ci- ⁇ alkyloxy
  • R5, R6 and R7 each independently are hydrogen, halo, Ci ⁇ alkyl, Ci- ⁇ alkyloxy; or R5 and R6 taken together may also form a bivalent radical of formula :
  • R8 and R 9 each independently are hydrogen or Ci ⁇ alkyl;
  • R 10 is hydrogen, Ci-6alkylcarbonyl, Ci ⁇ alkyloxycarbonyl; and
  • m is 1 or 2.
  • halo is generic to fluoro, chloro, bromo and iodo
  • Ci- ⁇ alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl and the like
  • C2-6 lkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, and the like
  • C2-6alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 2 to 6 carbon atoms such as, for example, ethy
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
  • the latter can conveniently be obtained by treating the base form with such appropriate acid
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • the term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form.
  • stereochemically isomeric forms as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or /rc./ ⁇ -configuration and Cj- ⁇ alkenyl radicals may have the E- or Z-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
  • JV-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those /V-oxides wherein the piperidine-nitrogen is N-oxidized.
  • R 1 suitably is fluoro, chloro or bromo, preferably R 1 is chloro;
  • R 3 when not taken together with R 2 , suitably is Cj- ⁇ alkyl, preferably methyl; when R 2 and R 3 are taken together a bivalent radical of formula (b) is preferred;
  • Alk is suitably 1,2-ethanediyl, 1,3-propanediyl, or 1,4-butanediyl, preferably 1 ,3-propanediyl;
  • R 4 is suitably hydrogen or methoxy;
  • R5, R6 and R7 are suitably hydrogen, Ci ⁇ alkyl, Ci. ⁇ alkyloxy or chloro, preferably methyl, methoxy or hydrogen; or when R 5 and R 6 are taken together a bivalent radical of formula (d) or (e) is preferred, especially a radical of formula (d).
  • More interesting compounds are those interesting compounds wherein Alk is 1,3-propanediyl.
  • Preferred compounds are those more interesting compounds wherein R 5 , R 6 and R 7 are methoxy.
  • Also preferred compounds are those more interesting compounds wherein R 7 is hydrogen and R 5 and R 6 are taken together to form a radical of formula (d) wherein R 8 and R 9 are hydrogen.
  • R 5 and R 7 are methyl and R 6 is methoxy.
  • reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, distillation, crystallization, trituration and chromatography.
  • the compounds of formula (I) may be prepared by N-alkylating a piperidine of formula (II) with an intermediate of formula (III).
  • W 1 in the intermediate of formula (III) is an appropriate leaving group such as, for example, halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g. methanesulfonyloxy, toluenesulfonyloxy and the like leaving groups.
  • halo e.g. chloro, bromo or iodo
  • a sulfonyloxy group e.g. methanesulfonyloxy, toluenesulfonyloxy and the like leaving groups.
  • the compounds of formula (I) may also be prepared by the esterification of an alcohol of formula (IV) wherein R 4 and L are as defined hereinabove, with a carboxylic acid of formula (V) wherein R 1 , R 2 and R 3 are as defined hereinabove, or a functional derivative thereof, such as an acylhalide, a symmetrical or mixed anhydride or an ester, preferably an activated ester, following art-known procedures.
  • Suitable protecting groups comprise readily removable groups such as phenylmethyl and the like protective groups.
  • the compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
  • Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chlorobenzenecarboperoxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide.
  • Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • the intermediates of formula (II) may be derived from an appropriately substituted piperidine of formula (VIII) with an intermediate acid of formula (V) or a functional derivative thereof, following art-known ester forming procedures, and subsequently removing the protective group P, following art-known procedures.
  • P represents a readily removable protective group such as Ci ⁇ alkylcarbonyl, Ci ⁇ alkyloxycarbonyl, phenylmethyl and the like protective groups.
  • intermediate acids of formula (V) is disclosed in EP-0,389,037-A.
  • the intermediates of formula (Vl-a) may be prepared by reduction of an intermediate of formula (IX) with a suitable reducing agent such as, for example, a combination of platinum on activated carbon and hydrogen, in a reaction-inert solvent such as, for example, tetrahydrofuran.
  • Said intermediates of formula (IX) may be prepared by /V-alkylating a piperidine of formula (II) with an intermediate of formula (X) wherein W 1 is an appropriate leaving group, such as, for example, a halogen atom, in an analogous way as the compounds of formula (I) are prepared from intermediates (II) and (III).
  • the intermediates of formula (VIII'), wherein P 1 represents P as defined hereinabove as well as hydrogen, may be prepared by reduction of an intermediate of formula (XI) following art-known methods.
  • the intermediates of formula (VHP), wherein R 4 is Ci-6alkyloxy, said intermediates being represented by formula (VHT-a), and wherein R 4 and the hydroxyl group have a c ⁇ -configuration may be prepared by reduction of an intermediate of formula (Xl-a) using a reductive agent such as substituted borohydrides, e.g.
  • lithium potassium tris-sec- butylborohydride substituted aluminiumhydrides, lithium-tri-terr-butoxyaluminohydride and the like, in a reaction-inert solvent such as, for example, tetrahydrofuran. It may be advantageous to perform the reaction at a lower temperature, preferably at a temperature below -70°C Using stereochemically pure reagents said reduction may be performed in a stereospecific manner.
  • cis and trans diastereomeric racemates of the compounds of formula (I), or any of the other intermediates may also be resolved into their optical isomers, cis(+), cis(-), trans ⁇ +) and transi . -) by the application of art-known methodologies.
  • Diastereoisomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, and enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with enantiomerically pure acids or their enantiomerically pure derivatives.
  • the compounds of formula (I) and the intermediates of formula (II) and (VI), the N-oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess favourable intestinal motility stimulating properties.
  • the present compounds show significant motility enhancing effects on the small and large intestine. The latter properties are evidenced by the results obtained in the "Guinea Pig Ileum
  • the subject compounds may be formulated into various forms for administration purposes.
  • compositions of this invention an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor propo ⁇ ions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Acid addition salts of (I), (II) or (VI) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets
  • the subject compounds are useful to normalize or to improve the intestinal transit in subjects suffering from symptoms related to disturbed motility, e.g. a decreased peristalsis of the small and large intestine alone or in combination with delayed gastric emptying.
  • a method of treating warm-blooded animals suffering from motility disorders of the intestinal system such as, for example, constipation, pseudo-obstruction, intestinal atony, post-operative intestinal atony, irritable bowel syndrome (IBS), drug-induced delayed transit, and in particular impaired colonic transit.
  • Said method comprises the systemic administration of an effective intestinal stimulating amount of a compound of formula (I), a V-oxide, a pharmaceutically acceptable acid addition salt or a possible stereoisomeric form thereof, to warm-blooded animals.
  • a method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.
  • Example 1 a) Sodium borohydride (7.7 g) was added po ⁇ ionwise to a stirred solution of 3-methoxy-l-(phenylmethyl)-4-piperidinone (44.8 g) in ethanol (610 ml). Upon completion, the whole was cooled to room temperature and stirring was continued for 3 hours at room temperature. The reaction mixture was concentrated to a volume of about 150 ml. Water (300 ml) was added to the concentrate and all traces of ethanol were evaporated. After cooling, the mixture was extracted with diethylether. The extract was washed with water, dried, filtered and evaporated The oily residue was purified by column-chromatography over silica gel (eluent : CHCI3/CH3OH 96/4).
  • Example 2 a) A mixture of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (4.3 g) in thionyl chloride (100 ml) and CHCI3 (200 ml) was stirred and refluxed for 2 hours. The mixture was cooled and the solvent was evaporated. Toluene was added and evaporated again, yielding 4.8 g of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarbonyl chloride (100% crude residue) (intermediate 7).
  • Example 3 A mixture of cyclopropyl (4-amino-3-nitrophenyl) methanone (80 g), prepared as described in US-3,657,267, and concentrated HCl (420 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and water was added. The precipitate was filtered off, washed with water and dried, yielding 80 g (84.5%) of l-(4-amino-3- nitrophenyl)-4-chloro-l-butanone; mp. 150 °C (intermediate 10). b) A mixture of intermediate (9) (14.8 g), intermediate (10) (12.13 g) and (150 ml) was stirred for 20 hours at ⁇ 70 °C.
  • the separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated.
  • the residue was purified by column chromatography over silica gel (eluent : CH2Cl2/hexane/(CH3 ⁇ H/NH3) 50/42/3). The desired fractions were collected and the solvent was evaporated.
  • the residue (2.3 g) was purified by high-performance liquid chromatography over silica gel (eluent: CH2CI2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated.
  • the residue (1.2 g) was crystallized from diisopropyl ether.
  • the preparation was excited with single rectangular stimili [1 msec; 0.1 Hz; submaximal response (current leading to 80% of maximal reponse)] from a progammable stimulator. Contractions were measured isometrically. During the stabilization period of 30 min, the strips were repeatedly stretched to a tension of 2 g, in order to obtain a steady state tension of 1 g. Before starting the electrical stimulation, a cumulative dose response curve of acetylcholine was given. The electrical stimulation was started at supramaximal current to determine the maximal amplitude of the twitch responses.
  • Example 9 Motility of the colon in the conscious dog.
  • mice Female beagle dogs, weighing 7-17 kg, were implanted with isometric force transducers, under general anaesthesia and aseptic conditions. To study the colonic motility, transducers were sutured on the colon at 8, 16, 24 and 32 cm distance from the ileo- caecal- valve. Dogs were allowed a recovery period of at least two weeks. Experiments were started after a fasting period of ⁇ 20 hours, during which water was available ad libitum. During the experiments, dogs were free to move in their cages, using a telemetric (wireless) system. The cages were built in a special room, provided with glass pervious to light in one direction, i.e. the observator could see the dogs while the dogs could not see the observator.
  • composition examples The following formulations exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.
  • Active ingredient as used throughout these examples relates to a compound of formula (I), a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
  • Example 12 Film-coated tablets Preparation, of ablet.c.ore
  • a mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl- pyrrolidone in about 200 ml of water.
  • the wet powder mixture is sieved, dried and sieved again.
  • 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.
  • Example 13 Injectable solution

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

On décrit de nouveaux dérivés benzoates de la formule (I), les formes N-oxyde, les sels d'addition d'acide pharmacologiquement acceptables, ainsi que les formes stéréochimiquement isomères de ces dérivés. Dans cette formule, R1 représente halo ou alkylsulfonylamino C¿1-6?; soit R?2¿ représente hydrogène et R3 représente alkyle C¿1-6?, alcényle C2-6 ou alcynyle C2-6; soit R?2 et R3¿ pris ensemble forment un radical bivalent de formule -CH=CH- (a), -(CH¿2?)2- (b), ou -(CH2)3- (c); dans ces radicaux (a), (b) et (c), un ou deux atomes d'hydrogène peuvent être remplacés par alkyle C1-6; Alk représente alcanediyle C1-6; R?4¿ représente hydrogène ou alkyloxy C¿1-6?; R?5, R6 et R7? représentent chacun indépendamment hydrogène, halo, alkyle C1-6, alkyloxy C1-6, ou bien R?5 et R6¿ pris ensemble peuvent également former un radical bivalent de formule: -NR?8C(O)NR9¿-, -NH-C(NHR10)=N-, -O-(CH¿2?)m-O-; R?8 et R9¿ représentent chacun indépendamment hydrogène ou alkyle C¿1-6; R?10 représente hydrogène, alkylcarbonyle C¿1-6?, alkyloxycarobnyle C1-6; m vaut 1 ou 2. On décrit également des compositions pharmaceutiques comprenant ces composés, des procédés de préparation de ces composés et compositions, de même que l'utilisation de ceux-ci en tant que médicament, notamment dans le traitement de troubles intestinaux impliquant une baisse de la motricité du côlon.
PCT/EP1995/003690 1994-09-27 1995-09-19 Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle) WO1996010026A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
EP95933399A EP0784619B1 (fr) 1994-09-27 1995-09-19 Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle)
US08/809,502 US5872131A (en) 1994-09-27 1995-09-19 Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives
NZ293604A NZ293604A (en) 1994-09-27 1995-09-19 1-(benzoylalkyl)-(4-piperidinyl)benzoate derivatives and pharmaceutical compositions
PL95319998A PL182174B1 (pl) 1994-09-27 1995-09-19 srodek farmaceutyczny i sposób wytwarzania pochodnychbenzoesanu fenylo-okso-alkilo-(4-piperydynylu) PL PL
AU36080/95A AU702846B2 (en) 1994-09-27 1995-09-19 Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives
DE69508600T DE69508600T2 (de) 1994-09-27 1995-09-19 Phenyl-oxo-alkyl-(4-piperidinyl) benzoatderivate
CA002200579A CA2200579C (fr) 1994-09-27 1995-09-19 Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle)
BR9509035A BR9509035A (pt) 1994-09-27 1995-09-19 Derivados de benzoato de fenil-oxo-alquíl-(4-peperidinila)
DK95933399T DK0784619T3 (da) 1994-09-27 1995-09-19 Phenyloxoalkyl-(4-piperidinyl)benzoatderivater
JP51133796A JP3862750B2 (ja) 1994-09-27 1995-09-19 フェニル−オキソ−アルキル−（４−ピペリジニル）ベンゾエート誘導体
CZ1997919A CZ288942B6 (cs) 1994-09-27 1995-09-19 Deriváty fenyloxoalkyl (4-piperidinyl) benzoátu
MXPA/A/1997/002356A MXPA97002356A (en) 1994-09-27 1995-09-19 Derivatives of phenyl-oxy-alkyl- (4-piperidinyl) benzo
NO19971375A NO311673B1 (no) 1994-09-27 1997-03-24 Fenyl-okso-alkyl-(4-piperidinyl)benzoatderivater
FI971273A FI971273A (fi) 1994-09-27 1997-03-26 Fenyylialkyyli-(4-piperidinyyli)bentsoaattijohdannaisia
GR990401260T GR3030175T3 (en) 1994-09-27 1999-05-10 Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP94202791.3 1994-09-27
EP94202791 1994-09-27
US45477695A 1995-05-31 1995-05-31

Publications (1)

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WO1996010026A1 true WO1996010026A1 (fr) 1996-04-04

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PCT/EP1995/003690 WO1996010026A1 (fr) 1994-09-27 1995-09-19 Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle)

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US (1) US5872131A (fr)
EP (1) EP0784619B1 (fr)
JP (1) JP3862750B2 (fr)
KR (1) KR100388255B1 (fr)
CN (1) CN1068881C (fr)
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DE3810552A1 (de) * 1988-03-29 1989-10-19 Sandoz Ag Ester und amide von indol-, benzo(b)thiopen-, benzo(b)furancarbonsaeuren oder 4-amino-2-methoxy-benzolsaeuren mit n-heterocyclischen oder n-heterobicyclischen alkoholen oder aminen, verfahren zu deren herstellung sie enthaltende pharmazeutische zusammensetzungen sowie applikator zur verabreichung derselben
EP0389037A1 (fr) * 1989-03-22 1990-09-26 Janssen Pharmaceutica N.V. Dérivés du N-(hydroxy-3 pipéridinyl-4)(dihydrobenzofuranne, dihydro-2H-benzopyranne ou dihydrobenzodioxine)carboxamide
EP0445862A2 (fr) * 1990-03-06 1991-09-11 Janssen Pharmaceutica N.V. Dérivés de la N-(4-pipéridinyl-)-dihydrobenzofurane- ou de ca dihydro-2H-benzopyrannecarboxamide
WO1993003725A1 (fr) * 1991-08-20 1993-03-04 Smithkline Beecham Plc Antagonistes du recepteur 5-ht4
WO1994008995A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Derives heterocycliques condenses d'acide benzoique utilises comme antagonistes des recepteurs 5-ht¿4?

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EP0309043A2 (fr) * 1987-09-25 1989-03-29 Janssen Pharmaceutica N.V. N-(1-alkyl-3-hydroxy-4-pipéridinyl)benzamides
DE3810552A1 (de) * 1988-03-29 1989-10-19 Sandoz Ag Ester und amide von indol-, benzo(b)thiopen-, benzo(b)furancarbonsaeuren oder 4-amino-2-methoxy-benzolsaeuren mit n-heterocyclischen oder n-heterobicyclischen alkoholen oder aminen, verfahren zu deren herstellung sie enthaltende pharmazeutische zusammensetzungen sowie applikator zur verabreichung derselben
EP0389037A1 (fr) * 1989-03-22 1990-09-26 Janssen Pharmaceutica N.V. Dérivés du N-(hydroxy-3 pipéridinyl-4)(dihydrobenzofuranne, dihydro-2H-benzopyranne ou dihydrobenzodioxine)carboxamide
EP0445862A2 (fr) * 1990-03-06 1991-09-11 Janssen Pharmaceutica N.V. Dérivés de la N-(4-pipéridinyl-)-dihydrobenzofurane- ou de ca dihydro-2H-benzopyrannecarboxamide
WO1993003725A1 (fr) * 1991-08-20 1993-03-04 Smithkline Beecham Plc Antagonistes du recepteur 5-ht4
WO1994008995A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Derives heterocycliques condenses d'acide benzoique utilises comme antagonistes des recepteurs 5-ht¿4?

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003104203A1 (fr) * 2002-06-07 2003-12-18 Cortical Pty Ltd Molecules therapeutiques et procedes - 1
GB2405147A (en) * 2002-06-07 2005-02-23 Cortical Pty Ltd Therapeutic molecules and methods-1
GB2405147B (en) * 2002-06-07 2006-11-22 Cortical Pty Ltd Therapeutic molecules and methods-1
US7709514B2 (en) 2002-06-07 2010-05-04 Cortical Pty Ltd Therapeutic molecules and methods-1

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ZA958086B (en) 1997-03-26
AU702846B2 (en) 1999-03-04
FI971273A (fi) 1997-03-26
JP3862750B2 (ja) 2006-12-27
JPH10506117A (ja) 1998-06-16
BR9509035A (pt) 1997-10-14
DE69508600T2 (de) 1999-11-25
CA2200579C (fr) 2006-07-04
RU2154634C2 (ru) 2000-08-20
KR100388255B1 (ko) 2003-10-04
DK0784619T3 (da) 1999-10-11
US5872131A (en) 1999-02-16
GR3030175T3 (en) 1999-08-31
CN1068881C (zh) 2001-07-25
EP0784619A1 (fr) 1997-07-23
EP0784619B1 (fr) 1999-03-24
ES2133805T3 (es) 1999-09-16
CN1160401A (zh) 1997-09-24
DE69508600D1 (de) 1999-04-29

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